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Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600–mutant tumours
Author(s) -
Nebot Noelia,
Arkenau HendrikTobias,
Infante Jeffrey R.,
Chandler Jason C.,
Weickhardt Andrew,
Lickliter Jason D.,
Sarantopoulos John,
Gordon Michael S.,
Mak Gabriel,
StPierre Annie,
Tang Lihua,
Mookerjee Bijoyesh,
Carson Stanley W.,
Hayes Siobhan,
Grossmann Kenneth F.
Publication year - 2018
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13488
Subject(s) - dabrafenib , dosing , medicine , pharmacokinetics , pharmacodynamics , qt interval , pharmacology , placebo , tolerability , adverse effect , pathology , alternative medicine , vemurafenib , cancer , metastatic melanoma
Aims The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600–mutant tumours. Methods Part 1 of this phase 1, multicentre, 2‐part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib‐matched placebo on day −1, single‐dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24‐h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. Results Part 1 ( n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty‐one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, −1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg C max and AUC (0–∞) were ≈ 2‐fold higher than with single‐dose 150 mg. Day 8 AUC (0‐τ) with 300 mg BID was ≈ 2.7‐fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. Conclusion Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen.